Recovery and recycling of chiral tartaric acid resolving agents

ABSTRACT

A process for the recovery of substituted tartaric acid resolving agents from resolution process liquors comprising organic solvents, wherein the substituted tartaric acid derivatives are neutralised by adding a base, extracted into an aqueous phase and crystallized from the aqueous phase by addition of a mineral acid in the presence of an organic solvent.

This invention relates to a novel process for the recovery of chiralsubstituted tartaric acid resolving agents from process liquors in aform of sufficient purity to enable their recycle in the correspondingresolution process.

Chemical processes for the synthesis of optically active amine compoundsfrequently use optically active organic acid resolving agents to allowthe required enantiomer to be preferentially crystallised as a salt withthe resolving agent. The required optically active amine can then beregenerated by basification of the salt.

Particular examples of such resolution processes are found in thesynthesis of N-benzylpiperidines and tetrahydropyridine derivativeswhich are useful intermediates in the synthesis of(−)-trans-4-(4-fluorophenyl)-3-(3,4-methylenedioxyphenoxymethyl)piperidine and its salts, a drug having anti-depressive effects.

One such process is disclosed in patent WO 98/01424, which describes theresolution of a racemic tertiary amine intermediate to form theoptically pure salt of the required absolute configuration with asubstituted tartaric acid resolving agent. The optically active amine isregenerated by reaction of the salt with a suitable base to give thesubstituted tartaric acid as a salt in aqueous solution as a byproduct.

In WO 01/46148 a process for the manufacture of (−)trans piperidinecarbinols is disclosed wherein the racemic piperidine carbinol iscontacted with (−)ditoluol tartaric acid, followed by isolation of thecrystalline salt and regeneration of the ditoluoltartaric acid byaddition of an aqueous inorganic base.

According to the Japanese laid open application No. 09176115 opticallyactive tartaric acid derivatives can be recovered from a resolvingprocess for optically active aminopyrrolidones by treatment of the saltswith alkalis in water, followed by extraction of the aqueous layer withorganic solvents and addition of mineral acids to the aqueous layer.

Examples of resolving agents used in such resolution processes include(+)-di-O,O′-toluoyl-(D)-tartaric acid, (−)-di-O,O′-toluoyl-(L)-tartaricacid, (+)-di-O,O′-benzoyl-(D)-tartaric acid,(−)-di-O,O′-benzoyl-(L)-tartaric acid. Examples of such structures areshown in FIG. 1.

Such resolving agents are typically expensive to manufacture orpurchase.

Previous to this invention, methods used to recover substituted tartaricacid resolving agents have been found to give poor yields and low puritydue to the prevalence of unwanted esterification, transesterification,or de-esterification reactions. The poor efficiency of previously usedrecovery processes are also the result of the need to extract thesubstituted tartaric acid into a water-immiscible organic solvent, thento crystallise it from a different solvent with consequent extended timefor distillation. Such solvent exchange operations increase the lossesdue to the unwanted side reactions referred to above.

It is an object of the present invention to provide an improved processfor the recovery of substituted tartaric acid resolving agents fromresolution mother liquors comprising organic solvents.

We have found that this object is achieved by a process wherein thesubstituted tartaric acid derivatives are neutralised by adding a base,extracted into an aqueous phase and crystallised from the aqueous phaseby addition of a mineral acid in the presence of a water soluble organicco-solvent.

This invention relates to an efficient method for recovery of thesubstituted tartaric acid resolving agent from the resolution motherliquor or from the aqueous phase from regeneration of the chiral salt ina form which may be recycled for use in further resolution reactions.Accordingly, the term “mother liquor” as used herein means the processliquor from the resolution process as well as the process liquor of theregeneration process.

Typically such process liquors comprise one or more organic solvents inaddition to the resolving agent and the optically active amine. Typicalorganic solvents used for the resolving process are ketones, e.g.acetone, alcohols such as for instance methanol, aromatic hydrocarbons,e.g. toluene, ethers such as for instance tetrahydrofurane or mixturesthereof. Preferably the organic solvent is only poorly miscible withwater or water immiscible, if not a water miscible solvent needs to bedistilled of and replaced by a poorly water miscible or immisciblesolvent, e.g. toluene.

In this invention the mother liquor may be reacted, optionally aftersolvent exchange, with a suitable base to give a salt of the substitutedtartaric acid resolving agent which is dissolved in water to allowseparation from organic by-products which may be dissolved in a waterimmiscible organic solvent. The aqueous phase obtained contains thesubstituted tartaric acid resolving agent as its salt with the base andis similar in composition to the solution obtained from the regenerationof the optically active amine from its salt with the resolving agent.

The base used for neutralisation of the amine salt of the substitutedtartaric acid resolving agent may be a hydroxide, carbonate or hydrogencarbonate salt of an alkali or alkaline earth metal or optionallysubstituted ammonia. Preferably the base is sodium or potassiumcarbonate or hydrogen carbonate or ammonia. More preferably the base issodium hydrogen carbonate. The base is preferably added in the form ofan aqueous solution. The concentration of the base in the solutiondepends on the type of base used.

The co-solvent added to the aqueous solution containing the substitutedtartaric acid resolving agent may be any water soluble or partlywatersoluble organic solvent, preferably a C_(1 to 10)-alcohol, morepreferably 2-butanol.

The mineral acid may be any strong acid, preferably sulphuric,phosphoric, hydrochloric, hydrobromic or nitric acid, more preferablyhydrochloric acid. The mineral acid is added in amounts sufficient torecover tartaric acid derivative in the form of the free acid.

The recovery of the tartaric acid derivatives is typically carried outat 20 to 50° C. The product is filtered off and dried, typically underreduced pressure.

The process according to the present invention is particularlyadvantageous in the recovery of tartaric acid resolving agents frommother liquors in the manufacture of optically pure(+)-1-benzyl-3-hydroxymethyl-4-(-4-fluorophenyl)-1,2,3,6-tetrahydropyridine.

Unexpectedly it has been discovered that addition of a suitable organicsolvent together with a mineral acid results in crystallisation of thesubstituted tartaric acid resolving agent directly from the aqueousmixture, without the need for phase separation or solvent exchanges, andin a manner which is reproducible on a commercial scale.

A particularly advantageous feature of the present invention is theisolation of substituted tartaric acid resolving agent in a crystallineform of suitable purity for reuse in a resolution reaction withoutadditional purification. The substituted tartaric acid resolving agentis typically crystallised as a solvate with the co-solvent used, of apurity in excess of 95% excluding the residual solvent. The opticalpurity of the substituted tartaric acid resolving agent is notsignificantly affected by the recovery process.

The present invention includes use of such a solvate of the substitutedtartaric acid resolving agent in a resolution reaction.

EXAMPLES Example 1

A solution (16.1 liters) containing (+)-di-O,O′-toluoyl-(D)-tartaricacid (about 1106 g) and1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridinedissolved in methanol was concentrated by distillation of methanol anddiluted with toluene (5.0 kg). The mixture was warmed to 40° C. and 1 Msodium hydrogen carbonate solution (6.3 liters) was added slowly. Themixture was stirred for 30 minutes then the lower aqueous phasecontaining (+)-di-O,O′-toluoyl-(D)-tartaric acid as its disodium saltwas separated off. The organic phase was stirred with water (1.8 liters)at 40° C. for 30 minutes. The lower aqueous phase was separated off. Theaqueous phases were combined and 2-butanol (2.5 liters) was added. Themixture was warmed to 40° C. and hydrochloric acid (552 ml) was addedslowly. The mixture was cooled to 10° C. and stirred for 30 minutes thenthe solid (+)-di-O,O′-toluoyl-(D)-tartaric acid was collected byfiltration and washed twice with water (2×2.2 liters). The damp solidwas dried at 50° C. under reduced pressure.(+)-Di-O,O′-toluoyl-(D)-tartaric acid (1270 g) was obtained as its2-butanol solvate, HPLC assay 72%/28% retained solvent, 83% of theory.

Example 2

(+)-1-benzyl-3-hydroxymethyl-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine(+)-di-O,O′-p-toluoyl-D-tartrate (1.8 kg) was suspended in toluene (6.9liters). The mixture was warmed to 35° C. and 1 M sodium hydrogencarbonate solution (6.6 liters) was added slowly. The mixture wasstirred at 35 to 40° C. for 2 hours then the lower aqueous phasecontaining (+)-di-O,O′-toluoyl-(D)-tartaric acid as its disodium saltwas separated off. The organic phase was stirred with water (4.4 liters)at 35 to 40° C. for 30 minutes. The lower aqueous phase was separatedoff. The aqueous phases were combined and 2-butanol (2.9 liters) wasadded. The mixture was warmed to 40° C. and hydrochloric acid (720 ml)was added slowly. The mixture was cooled to 10° C. and stirred for 30minutes then the solid (+)-di-0,0′-toluoyl-(D)-tartaric acid wascollected by filtration and washed twice with water (2×1.8 liters). Thedamp solid was dried at 50° C. under reduced pressure (10-300 mbar).(+)-Di-O,O′-toluoyl-(D)-tartaric acid (1310 g) was obtained as its2-butanol solvate, HPLC assay 76%/24% retained solvent, 98% of theory.

1. A process for recovering a substituted tartaric acid resolving agentfrom a resolution process liquor, wherein the resolution process liquorcomprises an organic solvent, and a substituted tartaric acid resolvingagent of the formula:

said process comprising: A) adding a base to the resolution processliquor to neutralize the substituted tartaric acid resolving agent; B)extracting the liquor obtained in A) into an aqueous phase; and C)adding a mineral acid and a water soluble or partly water solubleorganic co-solvent to the aqueous phase obtained in B) to crystallize asubstituted tartaric acid resolving agent from the aqueous phase.
 2. Aprocess according to claim 1 wherein the substituted tartaric acidresolving agent is chosen from (+)-di-O,O′-toluoyl-(D)-tartaric acid,(−)-di-O,O′-toluoyl-(L)-tartaric acid, (+)-di-O,O′-benzoyl-(D)-tartaricacid, or (−)-di-O,O′-benzoyl-(L)-tartaric acid.
 3. A process accordingto claim 1 wherein the base is added as an aqueous solution.
 4. Aprocess according to claim 1 wherein the substituted tartaric acidresolving agent is neutralized by a hydroxide, carbonate or hydrogencarbonate salt of an alkali or alkaline earth metal or ammonia.
 5. Aprocess according to claim 1 wherein the organic co-solvent is aC_(1 to 10)-alcohol.
 6. A process according to claim 1 wherein theorganic co-solvent is 2-butanol.
 7. A process according to claim 1wherein the mineral acid is hydrochloric acid, hydrobromic acid, orsulfuric acid.
 8. A process according to claim 1 wherein the mineralacid is hydrochloric acid.
 9. A process according to claim 1 wherein thesubstituted tartaric acid resolving agent is crystallised in the form ofa solvate with the co-solvent.